Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath win 2009 Nobel Prize in Chemistry

Welcome visitors coming from a recommendation by Dr Carmen Drahl at C&ENtral Science, the blog of the American Chemical Society's Chemical & Engineering News (C&EN):

Terra Sig has a fantastic post about the chemistry prize. The money quote: "If I see electrons being pushed around, it's chemistry."

Thank you for the kind words, Dr Drahl. New readers, feel free to weigh in down in the comments as to your take on this year's Chemistry prize.

The 2009 Nobel Prize in Chemistry has been awarded to three amazing scientists who elucidated the chemical bond-by-chemical bond action of the cell's protein synthesis organelle, the ribosome. Each of the three laureates employed three-dimensional, X-ray crystallographic structures and naturally-occurring antibiotics to dissect the mysteries of the ribosome, making tremendous advances in our knowledge on the least understood process of the central dogma of molecular biology: protein synthesis.

Yes, friends: this year's Nobel Prize in Chemistry would not have been possible without the awesome power of natural products and the contributions of my natural products chemistry colleagues who provided Ramakrishnan, Steitz, and Yonath with the chemical tools for their work.

Literally dozens of these antibiotics are used clinically around the world and I guarantee that if you possess the relative wealth to have an internet connection to read this, you have taken at least one of these antibiotics.

Tetracycline? Check. Erythromycin or azithromycin? Check.

The scientific background on the 2009 Nobel Prize in Chemistry (PDF) is, as always, the best place for advanced students to start reading about the context of the scientific achievements of the three laureates. These are terrific, underappreciated, and meticulously constructed review articles, and this one by Måns Ehrenberg is no exception. Page 14, for example, provides a detailed list of the antibiotics that target the small and large ribosomal subunits of bacteria.

I was surprised - maybe not - that while I consider myself knowledgeable about transcriptional regulation, my understanding of the mechanics of protein synthesis is comparatively woeful. I suspect this reflects my own training by people who traced their scientific roots to the masters of DNA synthesis and the antimetabolites chemotherapeutics that target DNA and RNA synthesis. And while we've all used the natural product cycloheximide (from Streptomyces griseus) as a protein synthesis inhibitor in laboratory experiments, how many of us really know how it works.

I digress, but I wanted to give the general reader an idea that many of us who study the chemistry of biology have spent far more time tackling other areas than the one for which today's prize is awarded.

And for those who claim that today's prize isn't "really" about chemistry, let me provide this paragraph from p. 4 of the Nobel background narrative that sets these discoveries in context:

Long standing mysteries in ribosome function. From this brief account of ribosome function it follows that the ribosome catalyzes two chemical reaction steps involving covalent bonds: peptide bond formation and ester bond hydrolysis during termination. . .

. . .The chemical mechanisms of the covalent reaction steps carried out by the ribosome remained mysterious during decades of intense work on the bacterial ribosome by a large number of groups. How tRNAs and class-1 release factors manage to discriminate so precisely between their cognate and near-cognate codons in a ribosome dependent manner were other unanswered questions. Finally, how antibiotic drugs and ribosomal mutations can tune the accuracy of codon reading up or down have also remained obscure. The clarification of these and other central questions concerning normal ribosome function and how ribosome function is perturbed by the action of antibiotic drugs or mutations depended on the advent of crystal structures at high resolution of ribosomal subunits, the whole ribosome and important functional complexes of the ribosome, its subunits and, finally, of the 70S ribosome itself.

If that's too complicated, how about this figure from p. 12:

The acid test: if I see electrons being pushed around, it's chemistry.

Let me close with this very serious issue because, after all, chemistry is life.

These discoveries have focused on mechanisms of basic cellular action - the distinctions between bacterial and eukaryotic ribosomal function have provided us with antibiotics that have arguably been the single greatest contribution to the increase in life expectancy that occurred in the 20th century. Unfortunately, bacteria evolve much faster than we do and antibiotic resistance is an increasingly life-threatening problem around the world, especially as drug-resistant strains previously restricted to hospitals are now acquired in the community.

Ehrenberg notes:

In the years after the Second World War, the wide spread introduction of antibiotics to treat bacterial infections revolutionized medicine and dramatically improved the health condition on a global scale. Now, 60 years later, the ever evolving antibiotic resistance among pathogens has heavily depleted the arsenal of effective antibiotic drugs. We seem to be running out of options, and a return to the pitiful health conditions preceding the Second World War has become an ominous scenario. About 90 000 patients in the USA die yearly as a result of bacterial infections compared to only about 13 000 twenty years ago, and in the majority of these casualties antibiotic resistance is an aggravating factor.

In recent years structure-based drug design (SBDD), where high resolution structures of drug targets and their resistance mutants are used to create novel drugs, has scored some promising successes, e.g. in the quest against HIV-virus infections. The ribosome is the target for about 50% of all antibacterial drugs to date, and the advent of high resolution structures of both ribosomal subunits has opened a large number of possibilities for SBDD of new and effective drugs in the race against resistance development among bacterial pathogens.

The meticulous dissection of ribosomal action by each of the laureates and their research teams has given us insight into the chemical mechanisms of action in protein synthesis, revealing the precise action of targets and how new compounds might be designed to overcome resistance. A number of us in so-called technologically-advanced nations have lost friends and loved ones to infectious diseases, even today.

The work of today's laureates is already influencing the discovery and design of novel antibiotics to combat drug-resistant bacteria and viral strains.

Heartiest to congratulations to Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath and, very importantly, their laboratory colleagues past and present.